insight into the pathogenesis of human vesico-ureteral reflux, or VUR. In addition, several novel clefting loci were identified which suggest new molecular mechanisms for palatal craniofacial development. Lastly, we identified a novel component of the mammalian RNA processing or P-body that regulates lens formation. These results confirm the power of this approach to establish causality for DGAP candidate genes. In the next grant period, we will extend this functional genomics approach and pursue more in-depth phenotype analyses. Furthermore, targeted mutations in most mouse genes will likely be attained during the next grant period. Therefore, the emphasis of Project 3 will now begin to shift from preparing conventional null alleles for DGAP candidate genes to making use of existing mouse models, preparing conditional alleles where required, and to pursuing more detailed phenotype analyses. In Aim 1, we will pursue new mouse mutational technology that is higher throughput than conventional gene targeting. Alternatively, in select cases, we will undertake a morpholino knockdown approach in zebrafish. In Aim 2, we will conduct marker gene experiments, genetic intercrosses and molecular experiments to establish causation, place genes into evolving pathways and identify the relevant developmental mechanisms. The overall goals of Project 3 continue and will be expanded in the future. The successful approach remains to delineate the developmental functions of new genes, and to provide definitive proof that mutations in these human genes produce birth defects. RELEVANCE (See instructions): The Developmental Genome Anatomy Project studies a group of patients underserved by the health care system: those with congenital abnormalities due to chromosome rearrangements. Our mission is to discover genes of importance in human development that are disrupted by these chromosomal rearrangements, genes that are difficult to identify by more traditional human genetic strategies, thereby opening investigation of the disorders that they cause. PROJECT/